Fusion of a Sequence from <i>HEI10</i> (14q11) to the <i>HMGIC</i> Gene at 12ql5 in a Uterine Leiomyoma

Mine, Nobuya; Kurose, Kouichi; Konishi, Hideyuki; Araki, Tsutomu; Nagai, Hisaki; Emi, Mitsuru

doi:10.1111/j.1349-7006.2001.tb01075.x

Cited by 37 publications

(17 citation statements)

References 17 publications

(22 reference statements)

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“…The N-terminal part of HEI10 interacts with the UbcH7 E2 ubiquitin conjugating enzyme and both interacts with and controls the accumulation of cyclin B, a key protein in cell cycle control (Toby et al, 2003). The HEI10 gene is a component of a translocation fusion to the HMG1C gene in uterine leiomyoma (Mine et al, 2001) and altered HEI10 expression has been seen in melanomas (Smith et al, 2004). These results imply that the deregulation of HEI10 may have consequences for tumor development.…”

Section: Introductionmentioning

confidence: 85%

A functional association between merlin and HEI10, a cell cycle regulator

et al. 2006

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Merlin and ezrin are homologous proteins with opposite effects on neoplastic growth. Merlin is a tumor suppressor inactivated in the neurofibromatosis 2 disease, whereas upregulated ezrin expression is associated with increased malignancy. Merlin's tumor suppressor mechanism is not known, although participation in cell cycle regulation has been suggested. To characterize merlin's biological activities, we screened for molecules that would interact with merlin but not ezrin. We identified the cyclin Bbinding protein and cell cycle regulator HEI10 as a novel merlin-binding partner. The interaction is mediated by the alpha-helical domain in merlin and the coiled-coil domain in HEI10 and requires conformational opening of merlin. The two proteins show partial subcellular colocalization, which depends on cell cycle stage and cell adhesion. Comparison of Schwann cells and schwannoma cultures demonstrated that the distribution of HEI10 depends on merlin expression. In transfected cells, a constitutively open merlin construct affected HEI10 protein integrity. These results link merlin to the cell cycle control machinery and may help to understand its tumor suppressor function.

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Section: Introductionmentioning

confidence: 85%

A functional association between merlin and HEI10, a cell cycle regulator

et al. 2006

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“…The HEI10 gene resides on human chromosome 14q11.1 and encompasses HEI10 within three exons. Of potential interest, one recent report has demonstrated that HEI10 is a component of a translocation fusion to the HMGIC gene in a uterine leiomyoma (37), whereas some studies have suggested involvement of this locus in the development of additional cancers. Two pseudogenes for HEI10 (based on 85 to 90% overall sequence homology, coupled with the lack of internal splice sites) exist: one at 20q11.2-13.2 and one at 1p34.…”

Section: Resultsmentioning

confidence: 99%

A Novel RING Finger Protein, Human Enhancer of Invasion 10, Alters Mitotic Progression through Regulation of Cyclin B Levels

Toby

Gherraby

Coleman

et al. 2003

Molecular and Cellular Biology

101

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The process of cellular morphogenesis is highly conserved in eukaryotes and is dependent upon the function of proteins that are centrally involved in specification of the cell cycle. The human enhancer of invasion clone 10 (HEI10) protein was identified from a HeLa cell library based on its ability to promote yeast agar invasion and filamentation. Through two-hybrid screening, the mitotic cyclin B1 and an E2 ubiquitin-conjugating enzyme were isolated as HEI10-interacting proteins. Mutation of the HEI10 divergent RING finger motif (characteristic of E3 ubiquitin ligases) and Cdc2/cyclin binding and phosphorylation sites alter HEI10-dependent yeast phenotypes, including delay in G 2 /M transition. In vertebrates, the addition of HEI10 inhibits nuclear envelope breakdown and mitotic entry in Xenopus egg extracts. Mechanistically, HEI10 expression reduces cyclin B levels in cycling Xenopus eggs and reduces levels of the cyclin B ortholog Clb2p in yeast. HEI10 is itself a specific in vitro substrate of purified cyclin B/cdc2, with a TPVR motif as primary phosphorylation site. Finally, HEI10 is itself ubiquitinated in egg extracts and is also autoubiquitinated in vitro. These and other points lead to a model in which HEI10 defines a divergent class of E3 ubiquitin ligase, functioning in progression through G 2 /M.The spatial and temporal regulation of cell division is essential for development and normal cellular replacement in both unicellular and multicellular organisms. Cell cycle control and cell morphology are coordinated by complex signaling networks, the inappropriate perturbation of which can lead to either programmed cell death (apoptosis) or indefinite cell division cycles (cancer). The fact that many protein constituents of such pathways are conserved over great phylogenetic distances among eukaryotes emphasizes their importance. Since the 1980s, complementation studies in which human genes were identified based on the specific rescue of, or genetic interaction with, orthologous pathways in yeast have proven to be a fruitful means of gaining insight into mammalian growth controls. For example, the central cell cycle kinases CDC2 (32) and CDK2 (11) and the C, D, and E cyclins (15,24,53,57) were identified by complementation of yeast mutants.Analysis of yeast budding controls has been of particular interest as a model of cellular morphogenesis and has provided an interpretive framework for studies of signal transduction and morphological control processes in less experimentally amenable multicellular organisms (see, for example, reference 26). Bud emergence in vegetatively growing yeast is a complex process that depends on the rearrangement of the cytoskeleton throughout the different phases of the cell cycle (8, 56). The site of bud emergence is specified by signals that mark the location of a previous bud. In addition to the spatial regulation of budding, bud emergence is temporally synchronized with the different phases of the cell cycle and is sensitive to the environment. A coordinated response to change...

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“…These mRNAs are structurally similar to those formed by gene fusion, typically consisting of HMGA2 exons 1-3 fused to intronic sequences from the same gene. 8,26 These mRNA variants have been found in all the tumor types described above. 8,[26][27][28][29] These findings, and the fact that there is no obvious functional relationship between the various partner genes, suggest that overexpression of the N-terminal part of HMGA2 may be the critical transforming event in tumors with 12q13 rearrangements, rather than the formation of particular fusion genes.…”

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confidence: 99%

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

et al. 2004

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Chromosomal translocations that target HMGA2 at chromosome band 12q14 are seen in a variety of malignancies, notably lipoma, pleomorphic salivary adenoma and uterine leiomyoma. Although some HMGA2 fusion genes have been reported, several lines of evidence suggest that the critical pathogenic event is the expression of truncated HMGA2 isoforms. We report here the involvement of HMGA2 in six patients with myeloid neoplasia, dysplastic features and translocations or an inversion involving chromosome bands 12q13-15 and either 7p12, 8q22, 11q23, 12p11, 14q31 or 20q11. Breaks within or very close to HMGA2 were found in all six cases by molecular cytogenetic analysis, leading to overexpression of this gene as assessed by RT-PCR. Truncated transcripts consisting of HMGA2 exons 1-2 or exons 1-3 spliced to intron-derived sequences were identified in two patients, but were not seen in controls. These findings suggest that abnormalities of HMGA2 play an important and previously unsuspected role in myelodysplasia.

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Fusion of a Sequence from HEI10 (14q11) to the HMGIC Gene at 12ql5 in a Uterine Leiomyoma

Cited by 37 publications

References 17 publications

A functional association between merlin and HEI10, a cell cycle regulator

A functional association between merlin and HEI10, a cell cycle regulator

A Novel RING Finger Protein, Human Enhancer of Invasion 10, Alters Mitotic Progression through Regulation of Cyclin B Levels

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

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